JPH10130262A - Benzothiophene compound, intermediate, process, composition and method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new benzothiophene compound useful for reducing symptom of bone loss or bone absorption, especially osteoporosis, a pathological condition relating to cardiovascular, etc. SOLUTION: This benzothiophene compound is a compound of formula I [R<1> is H, OH, O(1-4C alkyl), etc.; R<2> is H, Cl, F, OH, O(1-4C alkyl), etc.; R<3> is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, etc.; R<4> is H, a 1-5C alkyl, etc.; (n) is 2 or 3], e.g. 2-(4-methoxyphenoxy]-3-[N-[4-[2-(1-piperidinyl) ethoxyl]phenyl]acetamide]-6-methoxybenso[b]thiophene, etc. For example, the compound is obtained by using a compound of formula II (R<1a> is H, etc.; R<2a> is H, Cl, F, etc.) as a starting material, reacting the compound of formula II with a halogenation agent such as bromide in a solvent such as chloroform, and further reacting the resultant produce with 4-(protected hydroxy) phenylacylamide of formula III at about 40-80 deg.C for 1-6hr.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] Osteoporosis refers to a group of diseases that arise from a variety of etiologies, but are characterized by a net loss of bone mass per unit volume. The effect of this bone mass loss and the resulting fracture is a loss of the skeleton that provides adequate support to the body. One of the most common types of osteoporosis is associated with menopause. Most women have three to three
Within 6 years, about 20% to about 60% of the bone mass is lost in the trabecular compartment of the bone. This rapid loss is generally associated with increased bone resorption and formation. However, the resorption cycle is more dominant and the result is a net bone mass loss. Osteoporosis is a common and serious disease among postmenopausal women.

[0002] It is estimated that there are 250,000 women affected by the disease in the United States alone. The consequences of osteoporosis are personally harmful and also cause significant economic losses due to the need for extensive and long-term support (hospitalization and home care) due to its chronic and sequelae of the disease. This is especially true in older patients. In addition, although osteoporosis generally does not appear to be a life-threatening condition, a 20% to 30% mortality rate in elderly women is associated with hip fracture. This large percentage of mortality may be directly related to postmenopausal osteoporosis.

The most vulnerable tissue in bone for the effects of postmenopausal osteoporosis is trabecular bone. This tissue is often referred to as cancellous or cancellous bone and is particularly concentrated near the ends of the bone (near the joints) and in the vertebrae of the spine. Trabecular tissue is characterized by small osteoid structures that interconnect with each other, as well as by more rigid and dense cortical tissue that makes up the outer surface and central trunk of bone. This interconnected network of trabeculae provides lateral support to the cortical structure and is important for the biomechanical strength of the overall structure. In postmenopausal osteoporosis,
Primarily, the net absorption and loss of trabeculae results in bone loss and fracture. In view of trabecular loss in postmenopausal women, the most common fractures are highly dependent on trabecular support, such as the vertebrae, the neck of the weight-bearing bone, such as the femur and the forearm. It is not surprising that a fracture is relevant. In fact, hip fracture, Collies fracture,
Vertebral contusion fractures are characteristic of postmenopausal osteoporosis.

[0004] The most commonly accepted method of treating postmenopausal osteoporosis is estrogen replacement therapy. Although therapy is generally successful, patient compliance with the therapy is low, primarily because estrogen treatment frequently causes undesirable side effects. A further method of treatment would be the administration of a bisphosphonate compound such as, for example, Fosamax ™ (Merck & Co., Inc.).

[0005] Throughout pre-menopause, most women have a lower incidence of cardiovascular disease than men of the same age.
However, after menopause, the rate of cardiovascular disease in women gradually increases, comparable to that seen in men. This loss of protection is associated with a loss of estrogen and, in particular, a loss of estrogen's ability to regulate serum lipid levels. Although the nature of estrogen's ability to modulate serum lipids is poorly understood, evidence to date suggests that estrogen can upregulate low density lipid (LDL) receptors in the liver to remove excess cholesterol. Is shown. In addition, estrogen appears to have certain effects on cholesterol biosynthesis and other beneficial effects on cardiovascular health.

[0006] It has been reported in the literature that serum lipid levels in postmenopausal women receiving estrogen replacement therapy return to the levels found in premenopausal conditions. Thus, estrogen appears to be a reasonable treatment for this condition. However, the side effects of estrogen replacement therapy are unacceptable for many women, thus limiting the use of this therapy. The ideal therapy for this condition would be a substance that regulates serum lipid levels in a manner similar to estrogen, but without the side effects and dangers associated with estrogen therapy.

The present invention relates to a benzo [b] thiophene compound,
Pharmaceutical formulations and methods of using such compounds to control the above-mentioned conditions are provided.

The present invention provides a compound of formula I:

Embedded image Wherein R ¹ is —H, —OH, —O (C ₁ -C ₄ alkyl), —OCOAr, —O (CO) OAr (Ar is phenyl or substituted phenyl), —OCO (C ₁ − C ₆ alkyl), —O (CO) O (C ₁ -C ₆ alkyl), or —O
SO ₂ (C ₂ -C ₆ alkyl); R ² is —H, —Cl,
_{-F, -OH, -O (C 1} -C 4 alkyl), - Ocoa
r, -O (CO) OAr ( Ar is phenyl or substituted _{phenyl), - OCO (C 1 -C} 6 alkyl), - O (C
O) O (C ₁ -C ₆ alkyl) or —OSO ₂ (C ₂ -C ₆ alkyl); R ³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, R ⁴ is —H, C ₁ -C ₅ alkyl, —C 4 -morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino;
OAr, - (CO) H, -CO (C 1 -C 6 alkyl), - S
O ₂ (C ₂ -C ₆ alkyl), or —SO ₂ Ar, wherein Ar is phenyl or substituted phenyl; and n is 2 or 3.], or a pharmaceutically acceptable salt thereof. Alternatively, it relates to a solvate.

The present invention is useful for preparing the pharmaceutically active compounds of the present invention and has the following formula II:

Embedded image Wherein R ^1a is —H or —OR ⁷ (R ⁷ is a hydroxy protecting group); R ^2a is —H, —Cl, —F, or —OR ⁷ (R ⁷ is a hydroxy protecting group) Is); R
^4a is -CO (C ₁ -C ₄ alkyl) or - (CO) is H; and R ⁶ is -H or R ⁸ (R ⁸ is able to selectively remove if the presence of -OR ⁷ Which is a possible hydroxy protecting group).

The present invention further provides compounds of formula VII useful in the synthesis of compounds of formula I:

Embedded image Wherein R ^1a , R ^2a , R ^4a , and n have the above meaning; and Q is a leaving group.

The present invention is further directed to pharmaceutical formulations containing a compound of formula I, and the amelioration of such compounds, such as bone loss or bone resorption, especially osteoporosis, cardiovascular related pathological conditions and the like. Regarding the use of

The general terms used in the description of the compounds described herein have their ordinary meaning. For example, “C ₁ -C ₆ alkyl” refers to 1-6, including methyl, ethyl, propyl, isopropyl, butyl, n-butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
A linear or branched aliphatic chain consisting of two carbon atoms. Similarly, - the term "OC ₁ -C ₄ alkyl" represents, for example, methoxy, ethoxy, n- propoxy, such as isopropoxy, and the like, a C ₁ -C ₄ alkyl group attached through an oxygen. Of these C ₁ -C ₄ alkoxy groups, methoxy is highly preferred.

The term "substituted phenyl" refers to C ₁ -C ₄
Represents an alkyl, -OC ₁ -C ₄ alkyl, hydroxy, nitro, chloro, fluoro, or one or a phenyl group having more substituents selected from tri (chloro or fluoro) the group consisting of methyl.

The term "hydroxy protecting group" contemplates many of the functionalities used in the literature to protect hydroxyl functions during a chemical sequence,
By removing this, phenol can be obtained.
This group includes acyls, mesylates, tosylates,
Benzyl, alkylsilyloxys such, would include C ₁ -C ₄ alkyl, and the like. Many reactions for the formation and removal of such protecting groups are described, for example, in Protective G.
roups in Organic Chemistry, Plenum Press (London and New York, 1973);
W., PropectiveGroups in Organic Synthesis, W
iley (New York, 1981); and The Peptid
es, Volume 1, Schrooder and Lubke, Academic Pre
ss (London and New York, 1965)
It is described in many standard books. Preferred methods for removing the R ⁷ hydroxy protecting group, especially methyl and alkylsilyloxy, are substantially as described in the Examples below.

The term "leaving group (Q)" means a chemical entity that can be displaced by an amino function by an SN ₂ reaction. Such a reaction is
Well known in the art and such groups will include halogens, mesylates, tosylates and the like. The preferred leaving group will be bromo.

The term "suppressing" includes its generally accepted meaning, which prevents progression, severity,
It includes preventing, suppressing, and delaying, stopping, or reversing, or ameliorating the resulting symptoms or effects.

The term "solvate" refers to an aggregate comprising one or more molecules of a solute, such as a compound of Formula I, together with one or more molecules of a solvent.

The compounds of the present invention are derivatives of a centrally located carbon, and are thus, for example, "-CO
- "," - CHOH- "or" -CH ₂ - "moiety, methanones, a derivative of methanol such, or methanes. For example, the compound of A-CO-B is [A] [B]
Will be named Methanone. In addition, the compounds of formula I are available from The American Chemical Society.
Derivatives of benzo [b] thiophene, named and numbered according to the Ring Index of y):

Embedded image

A preferred compound of the present invention is 2- (4-hydroxyphenyl) -3- [N- [4- [2- (1-piperidinyl) ethoxy] phenyl] amino] -6-hydroxybenzo [b] thiophene Hydrochloride, and 2- (4-methoxyphenyl) -3- [N- [4- [2- (1-piperidinyl) ethoxy] phenyl] amino] -6-methoxybenzo [b] thiophene dihydrochloride.

Several synthetic routes are available for preparing the compounds of the present invention. The first synthetic route is illustrated in Scheme I below. Starting materials for one route for preparing compounds of formula I according to the invention, formula II
Compounds of I are substantially described by Jones et al. In U.S. Patent Nos. 4,418,068 and 4,133,814.
(The disclosures of which are incorporated herein by reference). Formula III has the following structure:

Embedded image Wherein R ^1a and R ^2a are as defined above.

For compounds of formula III, the preferred R ⁷ substituent is methyl or methoxymethyl. R ^1a and R
Compounds wherein ^2a is each methoxy, as well as other derivatives, are prepared by the methods described by Jones et al., Supra.

The first step in the process of the present invention for preparing certain compounds of formula I is to selectively place a leaving group at the 3-position of the compound of formula III, the reaction product of the first step To 4-
Coupling with a (protected hydroxy) phenylacylamide (Formula V) and removing the hydroxy protecting group to generate the phenol of compound IIb. The steps are shown in Scheme I below.

Scheme I

Embedded image

In the first step of Scheme I, the appropriate leaving group is selectively located at the 3-position of the starting material of Formula III by standard methods. Suitable R ⁹ leaving groups include methanesulfonate, 4-bromobenzenesulfonate, toluenesulfonate, ethanesulfonate, isopropanesulfonate, 4-methoxybenzenesulfonate, 4-nitrobenzenesulfonate, 2-chlorobenzenesulfonate, triflate and the like. Includes sulfonates, halogens such as bromo, chloro, and iodo, and other relevant leaving groups. However, to ensure proper placement of the leaving group, the listed halogens are preferred, and bromo is particularly preferred.

The reaction of the present invention is performed using standard methods. For example, when using a preferred halogenating agent,
One equivalent of such a halogenating agent, preferably bromine, is reacted with one equivalent of a substrate of formula III in the presence of a suitable solvent, such as chloroform or acetic acid. The reaction is carried out at a temperature of about 40 ° C. to about 80 ° C., usually from 1 to 6
Complete in time.

The reaction product obtained from the previous process step, a compound of formula IV, is then converted to a 4- (protected) compound wherein, for example, R ^4a is — (CO) H or —CO (C ₁ -C ₄ alkyl). Hydroxy) phenylacylamide (Formula V)
R ⁸ forms a compound of formula II wherein the hydroxy protecting group is selectively removable. In general, 4-hydroxy protecting moiety of the phenol may be selectively removed without removing the R ⁷ moiety of the compound of formula II (if present), it may be any known protecting group. Preferred R ⁸ protecting group is benzyl. The 4- (protected hydroxy) phenylalkylamides are known compounds and can be prepared by standard methods. For example, a preferred reagent, for example, 4-benzyloxyphenylacetamide, can be synthesized from commercially available 4-benzyloxyaniline and acetic anhydride by methods known in the art.

This coupling reaction between IV and V is known in the art as an Ullmann-type reaction, and various standard methods are mentioned. [For example, Advanced Org
anicChemistry: Reactions, Mechanisms, and Stru
cture, 4th edition, 3-16 (edited by J. March, John Wiley)
& Sons, Inc., 1992); Jones, CD, J. Ch.
em. Soc. Perk. Trans. I, 4: 407 (1992)].

Some modifications of the standard Ullmann-type reaction have been attempted, for example by reacting aniline or anilinosulfamide with an aryl bromide in the presence of a copper catalyst, but are known as the Goldberg reaction. Only one variant worked. The details of this reaction are described below.

In general, equal amounts of the two aryl substrates are heated to reflux under an inert atmosphere in the presence of an equimolar amount of copper (I) oxide catalyst and a suitable solvent. Suitable catalyst copper (I)
Examples of salts include, but are not limited to, Cu ₂ O, Cu
I and Cu ₂ CO ₃ . Preferably, one equivalent of the compound of formula IV wherein R ⁹ is bromo is reacted with the same amount of 4-benzyloxyphenylacetamide in the presence of one equivalent of cuprous oxide.

Suitable solvents for this reaction are solvents or mixtures of solvents which remain inert throughout the reaction. In general, organic bases, especially hindered bases such as, for example, 2,4,6-collidine, are preferred solvents.

The temperature used at this stage must be sufficient to effect the completion of the coupling reaction and will affect the amount of time required for it. When the reaction mixture is heated to reflux under an inert atmosphere such as nitrogen, the reaction is usually
Complete in 0-120 hours.

Following the coupling reaction to form the compound of formula IIa, the compound of formula IIb is prepared by selective removal of the R ⁶ hydroxy protecting group by well-known reduction methods. It is essential that the method chosen, if present, will not affect the R ⁷ hydroxy protecting group.

R ⁸ is a preferred benzyl, wherein R ⁷ is
If present, and if methyl, the process steps of the present invention are carried out by standard hydrocracking methods. Generally, the substrate of formula IIa is added to a suitable solvent or mixture of solvents, followed by the addition of a proton donor to promote the reaction and a suitable hydrogenation catalyst.

Suitable catalysts include noble metals and oxides such as palladium oxide, platinum and rhodium supported on a carrier such as carbon or calcium carbonate. Of these, palladium supported on carbon, particularly palladium supported on 10% carbon, is preferred.

The solvent for this reaction is a solvent or a mixture of solvents that remains inert throughout the reaction. In general, ₁ -C ₄ aliphatic alcohols ethyl acetate and C, particularly preferably ethanol.

For the reaction of the present invention, hydrochloric acid serves as a suitable and preferred proton donor.

When carried out at ambient temperature and a hydrogen pressure in the range of about 30 psi to about 50 psi, the reaction of the present invention proceeds very quickly. The progress of the reaction can be monitored by standard chromatographic techniques, such as thin layer chromatography.

Compounds of formula IIa and IIb are included within the classes described herein as compounds of formula II and are useful for preparing pharmaceutically active compounds of formula I.

Examples of compounds of formula II include, but are not limited to: 2- (4-methoxyphenyl) -3- [N- (4-hydroxyphenyl) acetamido]- 6-methoxybenzo [b] thiophene, 2-phenyl-3- [N- (4-hydroxyphenyl) acetamido] -6-methoxybenzo [b] thiophene, 2- (4-
Fluorophenyl) -3- [N- (4-hydroxyphenyl) acetamido] -6-methoxybenzo [b] thiophene, 2- (4-chlorophenyl) -3- [N- (4-hydroxyphenyl) acetamido] -6 -Methoxybenzo [b]
Thiophene, 2- (4-methoxyphenyl) -3- [N-
(4-benzyloxyphenyl) acetamido] -6-methoxybenzo [b] thiophene, 2-phenyl-3- [N
-(4-benzyloxyphenyl) acetamide] -6-
Methoxybenzo [b] thiophene, 2- (4-methoxyphenyl) -3- [N- (4-hydroxyphenyl) propanoylamide] -6-methoxybenzo [b] thiophene,
-(4-methoxyphenyl) -3- [N- (4-benzyloxyphenyl) butanoylamide] -6-methoxybenzo
[b] thiophene, 2- (4-chlorophenyl) -3- [N
-(4-benzyloxyphenyl) acetamido] benzo
[b] thiophene, 2- (4-methoxyphenyl) -3-
[N- (4-hydroxyphenyl) acetamido] benzo
[b] thiophene, 2- (4-methoxyphenyl) -3-
[N- (4-benzyloxyphenyl) acetamido] benzo [b] thiophene, 2- (4-methoxyphenyl) -3-
[N- (4-benzyloxyphenyl) formylamide] benzo [b] thiophene, 2- (4-fluorophenyl) -3
-[N- (4-benzyloxyphenyl) propanoylamido] benzo [b] thiophene and the like.

The compound of formula IIb can be converted to the compound of formula Ia by one of two different synthetic routes described in Scheme II below.

A first method is to use the formula VI: R ^3- (CH ₂ ) _n -Q VI wherein R ³ and n are as defined above; and Q is a deprotection such as bromo or chloro. Is the direct conversion of IIb to Ia by using the reagent of

Scheme II

Embedded image

The direct alkylation step shown in Scheme II is performed by standard methods. Compounds of formula VI are commercially available or are prepared by methods well known to those skilled in the art. Preferably, the hydrochloride of the compound of the formula VI, in particular 2-chloroethylpiperidine hydrochloride, is preferred.

Generally, at least about 1 equivalent of the substrate of formula IIb is reacted with 2 equivalents of the compound of formula VI in the presence of at least about 4 equivalents of an alkali metal carbonate, preferably cesium carbonate, and a suitable solvent.

The solvent for this reaction is a solvent or a mixture of solvents that remains inert throughout the reaction. N,
N-dimethylformamide, especially its anhydrous form, is preferred.

The temperature used at this stage must be sufficient to cause the completion of the alkylation reaction. Generally, ambient temperatures are sufficient and preferred.

The reaction of the present invention is preferably carried out in an inert atmosphere, especially under nitrogen.

Under the preferred reaction conditions, this reaction is carried out at about 16
It will be complete in ~ 20 hours. Of course, the progress of the reaction can be monitored by standard chromatographic techniques.

A second method for preparing compounds of formula Ia from compounds of formula IIb proceeds via an intermediate compound (formula VII) in a two-step sequence (Scheme VII).
II, see above). Alkaline solution, compounds excess of formula _{IIb: Q- (CH 2) n} -Q alkylation '[each wherein, Q and Q' are the same leaving group or different leaving group, React with the agent. Suitable leaving groups can be, for example, chloro, bromo, mesylate, tosylate and the like. A preferred alkaline solution for this alkylation reaction is, for example, methyl ethyl ketone (MEK)
Alternatively, potassium carbonate is contained in an inert solvent such as DMF. In this solution, the 4-hydroxy group of the phenyl moiety of the compound of formula IIb is present as a phenoxide ion replacing one of the leaving groups of the alkylating agent.

The reaction proceeds rapidly when the reaction is carried out to completion by setting the alkaline solution containing the reactants and reagents to the reflux temperature. When using MEK as the preferred solvent,
Reaction times range from about 6 hours to about 20 hours.

Compounds of formula VII are useful in the synthesis of compounds of formula I. Compounds of formula VII may include, but are not limited to: 2- (4-methoxyphenyl) -3- [N- [4- (2-bromoethoxy) phenyl] Acetylamide] -6-methoxybenzo
[b] thiophene, 2-phenyl-3- [N- [4- (2-
Bromoethoxy) phenyl] acetylamido] -6-methoxybenzo [b] thiophene, 2- (4-methoxyphenyl) -3- [N- [4- (2-bromoethoxy) phenyl] acetylamido] benzo [b] Thiophene, 2- (4-methoxyphenyl) -3- [N- [4- (3-bromopropoxy)
Phenyl] acetylamido] -6-methoxybenzo [b] thiophene, 2- (4-methoxyphenyl) -3- [N- [4
-(2-chloroethoxy) phenyl] acetylamide] -6
-Methoxybenzo [b] thiophene, 2- (4-methoxyphenyl) -3- [N- [4- (2-tosylethoxy) phenyl] acetylamide] -6-methoxybenzo [b] thiophene, 2- (4 -Methoxyphenyl) -3- [N- [4-
(2-Bromoethoxy) phenyl] butanoylamide] -6
-Methoxybenzo [b] thiophene, 2- (4-methoxyphenyl) -3- [N- [4- (2-bromoethoxy) phenyl] formylamide] -6-methoxybenzo [b] thiophene and the like.

Next, the reaction product obtained from this stage
(Formula VII) can be converted to an amine (R ³ ) by standard techniques, for example, 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidine, dimethyl-1-pyrrolidine, 4-morpholine, dimethylamine, diethylamine, diisopropyl Reaction with an amine, or 1-hexamethyleneimine, forms a compound of formula Ia. Preferably, anhydrous DM
In an inert solvent such as F, the hydrochloride of piperidine is converted to a compound of formula VII
And heated to a temperature in the range of about 60C to about 110C. If the mixture is heated to a preferred temperature of about 90 ° C., the reaction will take from about 30 minutes to about 1 minute.
It only takes time. However, changes in reaction conditions will affect the amount of time required to complete the reaction to completion. Of course, the progress of this reaction step can be monitored by standard chromatographic techniques.

The conversion of a compound of formula Ia to another compound of formula I is shown in Scheme III and may include the following steps: N-formation to form a diarylamino group (Ib)
Removal of the acyl group, another acyl or sulfonyl group (I
Removal and re-introduction to form c) or reduction of the N-acyl to the N-alkyl group (Id).

Scheme III

Embedded image

Removal of the N-acyl group from the compound of formula Ia is easily accomplished by hydrolysis of either the acid or the base to give Ib, wherein R ^1a , R ^2a , R ³ , and n
Has the meaning given above]. The preferred method involves heating the compound of formula Ia in an alcohol or concentrated alkoxide solution. Generally, Et
OH is used as the organic solvent and a 50% NaOH solution is used as the base source. The substrate is dissolved in an equal mixture of alcohol and base and heated to the reflux temperature of the mixed solvent. The reaction usually requires 6-24 hours to complete.

The compounds of formula Ib are pharmaceutically active for the methods described herein. Accordingly, such compounds are encompassed by the definition herein of compounds of formula I.

Further, the compound of the formula Ib has the formula Ic
R ^1a , R ^2a , R ³ , and n have the above meanings, and R ^4c is —CO (C ₁ -C ₆ alkyl), — (CO) H, —CO
Phenyl, -SO ₂ phenyl, or -SO ₂ (C ₂ -C ₆
Alkyl)). The nitrogen is acylated or sulfonated to form these compounds. This can be easily achieved by various acylation and alkylation methods well known in the art. As a further method for such acylation and sulfonation, the discussion on derivatization of phenols (see below) can be applied.

Compounds of formula Ia also have the formula Id wherein
R ^1a , R ^2a , R ³ and n have the above meanings and R ^4b is C ₁ -C ₅ alkyl]. This conversion can be achieved by reduction of the amide carbonyl in Ia to its corresponding methylene using a reducing reagent such as LAH. These reductions are known in the art and are usually performed in an inert solvent such as anhydrous THF, ether and the like. These reactions are carried out using an excess of a reducing reagent under a nitrogen atmosphere at -50 to
Perform at a temperature of 30 ° C. The reaction is usually completed within 2 to 24 hours and the extent of the reaction can be monitored using standard techniques such as TLC.

The compounds of the formulas Ia, Ib, Ic and Id are
It is pharmaceutically active for the methods described herein and is encompassed by Formula I as defined herein. In addition, compounds of Formula Ia-d may serve as substrates for other compounds of Formula I, for example, compounds wherein R ^1a and R ^2a have been converted to R ¹ and R ² , respectively.

Preferred compounds of the formula I are obtained by cleaving the R ⁷ hydroxy protecting group, if present, of the compounds of the formulas Ia-d by known methods. Many reactions for the formation and removal of such protecting groups include, for example,
Protrusive Groups in Organic Chemistry, Plenu
m Press (London and New York, 1973);
Green, TW., Proactive Groups in Organic Sy
nthesis, Willey (New York, 1981); and The Peptides, Volume 1, Schrooder and Lubke, A.
cademic Press (London and New York, 196
It has been described in many standard books, including 5). Preferred methods for removing the R ⁷ hydroxy protecting group, methyl, are substantially as described in the Examples below.

Other preferred compounds of formula I include, if present, a hydroxy moiety at the 6 and / or 4 'position, if present, of the formula -O-CO (C ₁ -C ₆ alkyl), -O
_{COC 6 H 5, -O (CO} ) O (C 1 -C 6 alkyl), or -O-SO ₂ - are prepared by converting the portion of the (C ₂ -C ₆ alkyl). Such methods are described in U.S. Patent Nos. 5,393,763 and 5,482,949, the disclosure of which is incorporated herein.

For example, if a —O—CO (C ₁ -C ₆ alkyl) group is desired, the mono- or dihydroxy compound of formula Ia-d can be combined with a material such as a chloride, bromide, cyanide, or acyl azide. Or with a suitable anhydride or mixed anhydride. The reaction is conveniently carried out in a basic solvent such as pyridine, lutidine, quinoline or isoquinoline, or in a tertiary amine solvent such as triethylamine, tributylamine, methylpiperidine and the like. The reaction is also performed with the addition of at least one equivalent of an acid scavenger (excluding those noted below), such as a tertiary amine, in ethyl acetate, dimethylformamide, dimethyl sulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone, methyl ethyl ketone. And the like. If desired, an acylation catalyst such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine can be used. For example, Haslam et al., Tetrah
edron, 36: 2409-2433 (1980).

The reactions of the present invention are often carried out under an inert atmosphere, such as nitrogen gas, at a suitable temperature ranging from about -25 ° C to about 100 ° C. But to do that reaction,
Usually, ambient temperature is appropriate.

The side reaction for acylating the bisaryl nitrogen (compound of formula Ib) does not use excess acylating reagent,
It can also be reduced by using lower temperatures. The undesired isomer is MeOH-CHCl
₃ Can be removed by chromatography on silica gel, eluting with a mixture of solvents, such as (1:99) (v / v) or an EtOAc-hexane mixture.

Acylation of the 6- and / or 4'-position hydroxy groups can also be carried out by an acid-catalyzed reaction of the appropriate carboxylic acid in an inert organic solvent. An acid catalyst such as sulfuric acid, polyphosphoric acid, methanesulfonic acid or the like is used.

The R ¹ and / or R ² groups of the aforementioned compounds of the formula Ia-d may also include dicyclohexylcarbodiimides, acylimidazoles, nitrophenols, pentachlorophenol, N-hydroxysuccinimide and 1-hydroxybenzotriazole. It can also be provided by forming an active ester of the appropriate acid, such as an ester formed by known reagents. For example, Bull. Chem. Soc. Japan, 38: 197.
9 (1965), and Chem. Ber., 788 and 2
024 (1970).

Each of the foregoing techniques for providing a —O—CO (C ₁ -C ₆ alkyl) moiety is performed in a solvent as discussed above. Techniques that do not produce an acid product during the reaction, of course, do not require the use of an acid scavenger in the reaction mixture.

When the compounds of (C ₂ -C ₆ alkyl) is converted based on the formula Ia-d is desired, - [0068] Formula hydroxy group of 6 and / or 4'-position of the compound of I is formula -O-SO ₂ King and Monoir, J. Am. Chem. Soc., 97: 2566-.
The mono- or dihydroxy compound is reacted with a derivative of a suitable sulfonic acid such as, for example, sulfonic anhydride, or a sulfonyl chloride, sulfonyl bromide, or sulfonyl ammonium salt, as taught by 2567 (1975). The dihydroxy compound can also be reacted with a suitable sulfonic anhydride or mixed sulfonic anhydride. Such reactions are performed under conditions as described above in the discussion of reactions with acid halides and the like.

The compounds of the formulas Ia-d, their phenolic hydroxyl compounds and their corresponding derivatized phenols constitute the compounds of the formula I according to the invention.

Examples of compounds of formula I include, but are not limited to: 2- (4-methoxyphenyl) -3- [N- [4- [2- (1- Piperidinyl) ethoxy] phenyl] acetamido] -6-methoxybenzo
[b] thiophene, 2- (4-hydroxyphenyl) -3-
[N- [4- [2- (1-piperidinyl) ethoxy] phenyl] acetamido] -6-hydroxybenzo [b] thiophene, 2- (4-methoxyphenyl) -3- [N- [4- [2
-(1-piperidinyl) ethoxy] phenyl] acetamido] -6-hydroxybenzo [b] thiophene, 2- (4-
(Hydroxyphenyl) -3- [N- [4- [2- (1-piperidinyl) ethoxy] phenyl] amino] -6-methoxybenzo [b] thiophene, 2- (4-methoxyphenyl) -3
-[N- [4- [2- (1-piperidinyl) ethoxy] phenyl] -N-ethylamino] -6-methoxybenzo [b] thiophene, 2- (4-methoxyphenyl) -3- [N- [ 4-
[2- (1-Piperidinyl) ethoxy] phenyl] propanoylamide] -6-methoxybenzo [b] thiophene,
-(4-methoxyphenyl) -3- [N- [4- [2- (1-
Piperidinyl) ethoxy] phenyl] acetamido] -6-
Methoxybenzo [b] thiophene, 2- (4-methoxyphenyl) -3- [N- [4- [3- (1-piperidinyl) propoxy] phenyl] acetamido] benzo [b] thiophene, 2- (4-methoxy Phenyl) -3- [N- [4- [2
-(1-Piperidinyl) ethoxy] phenyl] acetamido] -6-methoxybenzo [b] thiophene, 2- (4-methoxyphenyl) -3- [N- [4- [2- (1-pyrrolidinyl) ethoxy] phenyl ] Amino] -6-methoxybenzo
[b] thiophene, 2- (4-chlorophenyl) -3- [N
-[4- [3- (1-Hexamethylene) propoxy] phenyl] butanoylimide] -6-methoxybenzo [b] thiophene, 2-phenyl-3- [N- [4- [2- (1-piperidinyl) ethoxy] ] Phenyl] -N-methylamino] benzo
[b] thiophene, 2- (4-chlorophenyl) -3- [N
-[4- [3- (1-Pyrrolidinyl) propoxy] phenyl]
-N-butylamino] -6-hydroxybenzo [b] thiophene, 2- (4-acetyloxyphenyl) -3- [N
-[4- [2- (1-Piperidinyl) ethoxy] phenyl] acetamido] -6-methoxybenzo [b] thiophene,
-(4-methoxyphenyl) -3- [N- [4- [2- (1-
Piperidinyl) ethoxy] phenyl] acetamido] -6-
n-butylsulfonyloxybenzo [b] thiophene, 2
-Phenyl-3- [N- [4- [2- (1-piperidinyl)
Ethoxy] phenyl] acetamido] -6-benzoyloxybenzo [b] thiophene, 2- (4-benzoyloxyphenyl) -3- [N- [4- [3- (1-piperidinyl)
Propoxy] phenyl] acetamido] -6-methoxybenzo [b] thiophene, 2- (4-benzoyloxyphenyl) -3- [N- [4- [3- (1-hexamethyleneimino) propoxy] phenyl] -N -2-butylamino] -6
-Methoxybenzo [b] thiophene, 2- [4- (4-methoxybenzoyloxy) phenyl] -3- [N- [4- [2
-(1-piperidinyl) ethoxy] phenyl] -N-methylamino] -6-methoxybenzo [b] thiophene and the like.

While it is possible to use the compounds of the formula I in free base form in the process of the invention, it is preferable to prepare and use pharmaceutically acceptable salt forms. The term "pharmaceutically acceptable salts" refers to any of the acid or base addition salts known to be non-toxic and commonly used in the pharmaceutical literature. Pharmaceutically acceptable salts generally have enhanced solubility properties relative to the compound from which they are derived, and thus, as solutions or emulsions,
It is often easier to formulate. The compounds used in the methods of the present invention primarily form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids and are physiologically acceptable, often used in medicinal chemistry Contains salt. Such salts are also part of the present invention.

Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic,
Nitric acid, sulfuric acid, phosphoric acid, hypophosphoric acid and the like are included. Salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids and hydroxyalkane diacids, aromatic acids, aliphatic and aromatic sulfonic acids can also be used. Accordingly, such pharmaceutically acceptable salts include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxy Benzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, β-hydroxybutyrate, butyne-1,4 -Diacid, hexyne-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, Hippurate, lactate, malate, maleate, hydroxymalate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate,
Oxalate, phthalate, terephthalate, phosphate,
Monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate , Bisulfate, pyrosulfate,
Sulfite, bisulfite, sulfonate, benzene sulfonate, p-bromophenyl sulfonate, chlorobenzene sulfonate, ethane sulfonate, 2-hydroxyethane sulfonate, methane sulfonate, naphthalene-1 -Sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartrate and the like. A preferred salt is the hydrochloride salt.

Pharmaceutically acceptable acid addition salts are generally formed by reacting a compound of formula I with an equimolar or excess amount of an acid. The reactants are generally combined in a mutual solvent such as diethyl ether or ethyl acetate. The salt usually precipitates out of solution within about 1 hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional means.
ped off). The present invention further provides a pharmaceutically acceptable formulation for administration to a mammal, including a human, in need of treatment, comprising an effective amount of a compound of Formula I, and a pharmaceutically acceptable diluent. Alternatively, a formulation comprising a carrier is provided.

[0074] As used herein, the term "effective amount" refers to a pathology associated with cardiovascular disease, including bone loss or bone resorption, particularly osteoporosis, and hyperlipidemia and other cardiovascular conditions. A mammal is afflicted with a condition, including humans, which refers to the amount of a compound of the present invention that is capable of inhibiting, reducing, ameliorating, treating or preventing further symptoms.

In the case of estrogen-dependent cancer, the term “effective amount” refers to reducing, ameliorating, suppressing, treating cancer and / or its symptoms in mammals, including humans. Or the amount of a compound of the invention that can be prevented.

By the term "pharmaceutically acceptable formulation", the carriers, diluents, excipients and salts are the active ingredients of the formulation.
(Compound of formula I) and must not be toxic to the recipient. Pharmaceutical formulations can be manufactured by methods known in the art. For example, the compounds of the present invention can be formulated with common excipients, diluents, or carriers and formed into tablets, capsules, and the like. Examples of suitable excipients, diluents, and carriers for such formulations include: fillers and extenders, such as starch, sugars, mannitol and silicic acid derivatives; carboxymethyl cellulose and other Binders such as cellulose derivatives of alginates, gelatin and polyvinylpyrrolidone; wetting agents such as glycerol; disintegrating agents such as agar, calcium carbonate and sodium bicarbonate; substances which retard dissolution such as paraffin; Absorption enhancers such as quaternary ammonium compounds; Surfactants such as cetyl alcohol, glycerol monostearate; Adsorbent carriers such as kaolin and bentonite; and talc, calcium and magnesium stearate, and solid polyether. A lubricant, such as glycol. The final pharmaceutical form may be as follows: pill, tablet, powder, lozenge, syrup, aerosol, sachet, cachet, depending on the type of excipient used.
Elixirs, suspensions, emulsions, softeners, suppositories, sterile injectable solutions, sterile sealed powders, and the like.

In addition, the compounds of the present invention are well suited for formulation as sustained release dosage forms. The formulation may also be formulated to release the active ingredient only in certain parts of the intestinal tract, or preferably in certain parts of the intestinal tract, for as long as possible. Such formulations will require a coating, envelope, or protective matrix, which can be made from polymeric substances or waxes.

In accordance with the present invention, there is provided an individual compound of formula I required to treat, inhibit or prevent the symptoms and / or diseases of mammals, including humans, suffering from the preceding diseases. The dose will depend on the particular disease, condition, and severity. The dose, route of administration, and number of doses are best determined by the attending physician. Generally, an acceptable and effective dose is 15 mg to 3 times daily.
It will be 1000 mg, and more usually 15 mg to 80 mg. Such a dose would be
It will be administered for at least one month, and generally for six months, or longer.

The following formulations are given for illustrative purposes and are not intended to be limiting in any way.
The total active ingredient in such formulations comprises from 0.1% to 99.9% by weight of the formulation. The term “active ingredient” means a compound of the formula I.

[0080] Formulation Example 1: Gelatin Capsules Ingredient Quantity (mg / capsule) Active ingredient 0.1 - 1000 Starch, the NF 0 500 Starch flowable powder 0 - 500 Silicone fluid 350 centistokes 0 - 15 The components mixed Then, the mixture is passed through a No. 45 mesh US sieve and filled into hard gelatin capsules.

Formulation Example 2: Tablet component amount (mg / tablet) Active ingredient 2.5-1000 Starch 10-50 cellulose, microcrystalline 10-20 Polyvinylpyrrolidone (as 10% aqueous solution) 5 Sodium carboxymethylcellulose 5 Stearic acid Magnesium 1 Talc 1-5 The active ingredient, starch, and cellulose are passed through a No. 45 mesh US sieve and mixed thoroughly. After mixing the resulting powder with the polyvinylpyrrolidone solution, it is passed through a No. 14 mesh US sieve. The granules thus produced are dried at 50-60 ° C.
o Pass through a 18 mesh US sieve. No.60 in advance
Add sodium carboxymethylcellulose, magnesium stearate, and talc that have been passed through a mesh US sieve to the granules and mix thoroughly. The resulting material is compressed on a tablet machine to give tablets.

[0082] Formulation Example 3: Aerosol Ingredient Weight% Active ingredient 0.25 Ethanol 29.75 Propellant 22 (Chlorodifluoromethane) 70.00 Total 100.00 The active ingredient is mixed with ethanol and the mixture Add to a portion of Propellant 22, cool to -30 ° C,
Transfer to filling device. The required amount is then placed in a stainless steel container and diluted with the remaining propellant. Next, a valve device is attached to the container.

Formulation Example 4: Suppository Component Weight Active Ingredient 150 mg Saturated Fatty Acid Glyceride 3,000 mg Active ingredient is passed through a No. 60 mesh US sieve and heated to its melting point in fatty acid glyceride. Suspended in The mixture is poured into suppository molds and allowed to cool.

Formulation 5: Suspension A suspension containing 0.1 to 1,000 mg of a compound of formula I each per 5 ml dose. The compounds of formula I to Ingredient weight active ingredient 0.1-1,000mg Sodium carboxymethyl cellulose 50mg Syrup 1.25ml acid solution (0.1 M) 0.10 ml Perfume q.s. coloring qs Purified water total amount 5 ml No.45 Pass through a mesh US sieve and mix with sodium carboxymethylcellulose and syrup to form a smooth paste. Add the benzoic acid solution, flavor, and color diluted with water and stir the mixture thoroughly. Add more water to bring the formulation to final volume.

The following examples and formulation examples are provided to better illustrate the practice of the present invention and should not be construed as limiting its scope. Those skilled in the art will recognize that various modifications can be made without departing from the spirit and scope of the invention. All publications and patent applications mentioned in the specification are indicative of the level of those skilled in the art to which the invention pertains.

The NMR data for the following examples are G
E Obtained using a 300 MHz NMR instrument and unless otherwise indicated anhydrous CDCl ₃ was used as solvent. Electric field strength for ¹³ C NMR spectra was 75.5 MHz unless otherwise indicated.

Production Example 1 2- (4-methoxyphenyl) -3-bromo-6-methoxybenzo [b] thiophene 2- (4-methoxyphenyl) -6-methoxybenzo in 1.10 L of chloroform at 60 ° C. [b] Thiophene (2
7.0 g, 100 mmol) in 200 ml of chloroform.
Bromine (15.98 g, 100 mmol) dissolved in was added dropwise. After the addition was completed, the reaction was cooled to room temperature,
The solvent was removed under reduced pressure to give 2- (4-methoxyphenyl)
-3-Bromo-6-methoxybenzo [b] thiophene 3
4.2 g (100%) were obtained as a white solid. 83-85 ° C. _{^{1 H NMR (DMSO-d 6}} ) d 7.70-7.62
(m, 4H), 7.17 (dd, J = 8.6 Hz, 2.0 Hz, 1
H), 7.09 (d, J = 8.4 Hz, 2H). FD mass spec: 349, 350. Elemental analysis (as _{C 16 H 13 BrO 2 S)} : Calculated: C 55.03; H 3.75. Found: C, 54.79; H, 3.76.

Production Example 2 2- (4-methoxyphenyl) -3- [N- (4-benzyloxyphenyl) acetamido] -6-methoxybenzo
[b] thiophene under N ₂ in 2,4,6-collidine 100 ml 2-(4-methoxyphenyl) -3-bromo-6-methoxy-benzo [b]
Thiophene (34.20 g, 0.098 mol) and N-4
-Benzyloxyphenylacetamide (23.7 g,
0.098 mol) in a solution of Cu ₂ O (14.0 g, 0.098 mol).
mol) was added. The resulting mixture was heated to reflux for 72 hours. Upon cooling, the reaction was washed with CH ₂ Cl
_After dilution with ₂ , the precipitated solid material was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was dissolved in EtOAc. The organic layer was then extracted several times with 5.0N HCl. The organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to a solid. Chromatography (SiO ₂ ,
CHCl ₃ ) to give 2- (4-methoxyphenyl) -3
-[N- (4-benzyloxyphenyl) acetamide]-
2.43 g (5%) of 6-methoxybenzo [b] thiophene were obtained as an amber foam. _{^{1 H NMR (DMSO-d 6}} ) d ( doubling due to amide rotamers) 7.70-6.80 (m, 16H), 4.9
0 (bs, 2H), 3.78-3.75 (m, 6H), 2.11 and 1.78 (s, 3H). FD mass spec: 509.

Production Example 3 2- (4-methoxyphenyl) -3- [N- (4-hydroxyphenyl) acetamido] -6-methoxybenzo [b] thiophene 2- (4-methoxyphenyl) -3- [N -(4-benzyloxyphenyl) acetamido] -6-methoxybenzo
[b] Thiophene (2.43 g, 4.77 mmol) was dissolved in 50 ml of 1: 1 EtOH / EtOAc containing 5% concentrated HCl. To this solution was added 1.0 g of 5% Pd / C. The resulting mixture was hydrogenated at 40 psi for 4 hours. The mixture was then filtered through celite to remove the catalyst. The filtrate was concentrated under reduced pressure to a semi-solid material.
Chromatography (SiO ₂ , CHCl ₃ ) gave 2-
1.32 g (83%) of (4-methoxyphenyl) -3- [N- (4-hydroxyphenyl) acetamido] -6-methoxybenzo [b] thiophene were obtained as an amber foam. _{^{1 H NMR (DMSO-d 6}} ) d ( doubling due to amide rotamers) 9.53 and 9.36 (s, 1H), 7 .
62-6.51 (m, 11H), 3.78 and 3.58 (s,
6H), 2.01 and 1.76 (s, 3H). FD mass spec: 419. Elemental analysis (as _{C 24 H 21 NO 4 S ·} 0.19 CHCl 3): Calculated: C 65.71; H 4.83; N 3.17. Found: C, 65.80; H, 4.70; N, 3.01.

Example 1 2- (4-methoxyphenyl) -3- [N- [4- [2- (1
-Piperidinyl) ethoxy] phenyl] acetamido] -6
-Methoxybenzo [b] thiophene 2- (4-methoxyphenyl) -3 in 15 ml of anhydrous DMF
-[N- (4-hydroxyphenyl) acetamido] -6
Methoxybenzo [b] thiophene (1.31 g, 3.13 mmol
l) and Cs ₂ CO ₃ (4.10 g, 12.50 mmol) in a solution of 2-chloroethylpiperidine hydrochloride (1.15 g,
6.26 mmol) was added. The resulting mixture was stirred vigorously at room temperature for 5 hours. The reaction mixture is washed with H ₂ O 20
After dilution with 0 ml, it was extracted several times with EtOAc. Then
The combined organic layers were washed several times with H ₂ O and then dried
(Na ₂ SO ₄ ). Concentration under reduced pressure gave an oil. Chromatography _{(1% CH 3 OH / CHCl} 3, SiO 2)
To give 2- (4-methoxyphenyl) -3- [N- [4
-[2- (1-piperidinyl) ethoxy] phenyl] acetamido] -6-methoxybenzo [b] thiophene 1.49 g
(90%) was obtained as an amber oil. _{^{1 H NMR (DMSO-d 6}} ) d ( doubling due to amide rotamers) 7.66-6.70 (m, 11H), 3.9
3 (m, 2H), 3.78 and 3.58 (s, 6H), 2.8
-2.30 (m, 6H), 2.01 and 1.78 (s, 3
H), 1.52-1.11 (m, 6H). FD mass spectrometry: 530. Elemental analysis (as _{C 31 H 34 N 2 O 4} S): Calculated: C 70.16; H 6.46; N 5.28. Found: C, 70.33; H, 6.34; N, 5.35.

Example 2 2- (4-methoxyphenyl) -3- [N- [4- [2- (1
-Piperidinyl) ethoxy] phenyl] amino] -6-methoxybenzo [b] thiophene dihydrochloride 2- (4-methoxyphenyl)-in 10 ml of anhydrous EtOH
To a solution of 3- [N- [4- [2- (1-piperidinyl) ethoxy] phenyl] acetamido] -6-methoxybenzo [b] thiophene (1.49 g, 2.80 mmol) was added 50% NaOH.
10 ml of the solution were added. The resulting mixture was heated to reflux for 18 hours. Upon cooling, the mixture is
It was diluted with ₂ O 200ml. The aqueous layer was then extracted with EtOAc (3
× 100 ml). The organic layers were combined, washed with brine and dried (Na ₂ SO ₄ ). Concentration under reduced pressure gave a foam which was chromatographed (CHCl
₃ , SiO ₂ ). The isolated oil was converted to the hydrochloride salt by treatment with Et ₂ O.HCl in EtOAc. Isolated by filtration, 2- (4-methoxyphenyl) -3- [N- [4- [2- (1-piperidinyl) ethoxy] phenyl] amino] -6-methoxybenzo [b] thiophene hydrochloride 1. 37 g (100%) were obtained as a white solid. 126-130 ° C. ¹ H NMR (DMSO-d ₆ ) d 7.54 (d, J = 8.
8 Hz, 2 H), 7.48 (d, J = 2.2 Hz, 1 H), 7.2
9 (d, J = 8.9 Hz, 1 H), 6.92 (d, J = 8.8 Hz,
2H), 6.91 (dd, J = 8.9 Hz, 2.2 Hz, 1H),
6.73 (d, J = 8.9 Hz, 2H), 6.50 (d, J = 8.
9Hz, 2H), 4.21 (t, J = 4.7Hz, 2H), 3.7
8 (s, 3H), 3.71 (s, 3H), 3.43-3.31
(m, 4H), 2.97-2.90 (m, 2H), 1.80-1.
61 (m, 5H), 1.35 (m, 1H). FD mass spec: 488. Elemental analysis (as _{C 29 H 34 N 2 O 3} S · 2.0 HCl): Calculated: C 62.03; H 6.10; N 4.99. Found: C, 61.79; H, 6.35; N, 5.27.

Example 3 2- (4-hydroxyphenyl) -3- [N- [4- [2-
(1-Piperidinyl) ethoxy] phenyl] amino] -6
Hydroxybenzo [b] thiophene hydrochloride 2- (4- (4-N) in 40 ml of anhydrous CH ₂ Cl _{2 at} 10 ° C. under N _2.
Methoxyphenyl) -3- [N- [4- [2- (1-piperidinyl) ethoxy] phenyl] amino] -6-methoxybenzo [b] thiophene hydrochloride (0.70 g, 1.25 mmol) BBr ₃ (0.36 ml, 3.80 mmol) was added. The solution was gradually warmed to room temperature and stirred for a total of 6 hours.
The reaction was quenched by pouring the mixture into excess saturated NaHCO ₃ solution. Then, the aqueous layer is 5%
Extracted several times with EtOH / EtOAc. Combine the organic layers,
After drying (Na ₂ SO ₄ ), it was concentrated under reduced pressure to give a foam. The crude product was chromatographed (1-6).
% Over a _{CH 3 OH / CHCl 3),} 2- (4- hydroxyphenyl) -3- [N- [4- [2- (1- piperidinyl)
[Ethoxy] phenyl] amino] -6-hydroxybenzo
[b] 325 mg (49%) of thiophene was obtained as an oil. This material was converted to the hydrochloride salt by treatment with Et ₂ O.HCl in EtOAc and isolated by filtration as a white solid. 2- (4-hydroxyphenyl)-
3- [N- [4- [2- (1-piperidinyl) ethoxy] phenyl] amino] -6-hydroxybenzo [b] thiophene
Data for the hydrochloride salt: mp 140-150 ° C. ¹ H NMR (DMSO-d ₆ ) d 9.57 (s, 2H),
7.40 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 1
0.1 Hz, 1 H), 7.16 (d, J = 2.0 Hz, 1 H), 6.
75 (dd, J = 10.1 Hz, 2.0 Hz, 1H), 6.70
(d, J = 8.6 Hz, 2H), 6.64 (d, J = 8.8 Hz, 2
H), 6.46 (d, J = 8.8 Hz, 2H), 4.21 (m, 2
H), 3.50-3.30 (m, 4H), 3.01-2.95
(m, 2H), 1.81-1.63 (m, 5H), 1.38 (m,
1H). FD mass spec: 461. Elemental analysis (as _{C 27 H 28 N 2 O 3} S · 1.5 HCl): Calculated: C 62.94; H 5.77; N 5.44. Found: C, 62.99; H, 5.88; N, 5.27.

In an example illustrating the method, a postmenopausal model was used to determine the effect of various treatments on circulating lipids.

75-day-old female Sprague Dawley rat
(Weight 200-225g) with Charles River Laborato
ries (Portage, Michigan). The rats were left and right ovaries removed with Charles River Laboratories (OVX) or sent one week after undergoing Sham surgery. Upon arrival, they were housed in metal suspension cages in groups of three or four per cage and given food (calcium content about 0.5%) and water ad libitum for one week. Room temperature was maintained at 22.2 ± 1.7 ° C. with a minimum relative humidity of 40%. The light cycle in the room is 1
Light was turned on for 2 hours and dark for 12 hours.

Dosing Regime Tissue Collection After a one week acclimation period (thus two weeks later-OV
X), daily dosing with test compound was started. Unless otherwise stated, 17a-ethynylestradiol or test compound was given orally as a suspension in 1% carboxymethylcellulose or dissolved in 20% cyclodextrin. Rats were dosed daily for 4 days. Following the dosing regimen, rats were weighed, anesthetized with a ketamine: xylazine (2: 1, V: V) mixture, and blood samples were collected by cardiac puncture. The rats are then treated with CO ₂
The uterus was excised by midline incision and the wet weight of the uterus was measured.

Cholesterol analysis Blood samples were allowed to clot for 2 hours at room temperature and 10 minutes at 3000 rpm.
After centrifugation for minutes, serum was obtained. Boehringer Mannh
Serum cholesterol was measured using the high performance cholesterol assay from eim Diagnostics. Briefly, cholesterol is oxidized to cholester-4-ene-
3-one and hydrogen peroxide. The hydrogen peroxide is then converted to phenol and 4 in the presence of peroxidase.
-Reaction with -aminophenazone to form p-quinone imine dye, which was read at 500 nm by spectrophotometric analysis. Then, the cholesterol concentration was calculated using the standard curve as a control. Biomek Automated Workstatio
n was used to automate the entire assay.

Uterine eosinophil peroxidase (EPO)
The uterus was kept at 4 ° C. until the time of the enzyme assay. The uterus was then washed with 50% containing 0.005% Triton X-100.
Homogenized in 50 volumes of mM Tris buffer (pH 8.0). Add 0.01% hydrogen peroxide in Tris buffer and 10 mM O-phenylenediamine (final concentration)
The increase in absorbance was monitored at 450 nm for 1 minute. The presence of eosinophils in the uterus is an indicator of the compound's estrogenic activity. From the first linear portion of the response curve, the maximum velocity at 15 second intervals was measured.

Compound Source 17a-Ethynylestradiol was converted to Sigma Chemical
Co. (St. Louis, MO).

Compounds of formula I for serum cholesterol
Effect of and Measurement of Agonist / Non-Agonist Activity The data shown in Table 1 below are for ovarectomized rats, 1
7 shows comparative results between rats treated with 7a-ethynyl estradiol (EE ₂ ; an orally available form of estrogen) and rats treated with certain compounds of the present invention. EE ₂ , when given orally at a rate of 0.1 mg / kg / day, causes a decrease in serum cholesterol, but also shows a stimulatory effect on the uterus, so that EE ₂ uterine weight substantially reduces ovarian It is larger than the uterus weight of the excised test animal. This uterine response to estrogen is well recognized in the art.

The compounds of the present invention generally not only reduce serum cholesterol, but also increase uterine weight slightly, as compared to ovariectomized control animals, or show a slight increase in most of the test compounds of the formula. To reduce. The advantage of reducing serum cholesterol without adversely affecting uterine weight over estrogenic compounds known in the art is very rare and desirable.

Estrogenicity was also assessed by assessing the adverse response of eosinophil infiltration to the uterus, as shown in the data below. The compounds of the present invention do not cause any increase in the number of eosinophils observed in the stromal layer of ovariectomized rats, whereas estradiol does
Causes a substantial, expected increase in eosinophil wetting.

The data shown in Table 1 below reflects the response of 5 or 6 rats per treatment.

Table 1

[Table 1] a mg / kg PO. b Percentage uterine weight gain relative to ovarectomized control. c Eosinophil peroxidase, top rate. d Serum cholesterol reduction relative to ovariectomized controls. e 17a-ethynylestradiol * p <0.05

In addition to the demonstrated benefits of the compounds of the present invention,
The previous data indicate that the compound of formula I is an estrogen analog (mim
etics). In addition, no toxic toxicological effects (eg, survival numbers) were observed with any of the treatments.

Osteoporosis Test Method In the following general preparation, rats are treated daily for 35 days (6 rats per treatment group) and sacrificed on day 36 by asphyxiation with carbon dioxide. A period of 35 days is sufficient to reduce bone mineral density maximally and is measured as described herein. At the time of slaughter,
The uterus is excised, the attached tissue is dissected away, and the liquid contents are drained before measuring wet weight to confirm estrogen deficiency associated with complete ovariectomy. Ovariectomy usually reduces uterine weight by about 75%. Then
After soaking the uterus in 10% neutral buffered formalin,
Perform histological analysis.

The right thigh is excised, digitized X-rays are generated and an image analysis program at the distal metaphysis
(NIH image). Proximal aspects of the tibia from these rats are also scanned by quantitative computer-assisted tomography.

According to the above method, a compound of the present invention and ethinyl estradiol (EE ₂ ) in 20% hydroxypropyl β-cyclodextrin are administered orally to test animals. Data results for the distal femoral metaphysis and proximal tibia are reported as% protection compared to ovariectomy.

In summary, ovariectomy of the test animals caused a significant decrease in thigh density compared to intact, vehicle-treated control animals. Although ethinyl estradiol (EE ₂ ) administered orally prevents this loss, the risk of uterine irritation with this treatment remains.

The compounds of the invention also prevent bone loss in a general, dose-dependent manner. Accordingly, the compounds of the present invention are particularly useful for treating osteoporosis caused by postmenopausal syndrome.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/55 A61K 31/55 C07D 409/12 211 C07D 409/12 211 (72) Inventor Alan David Parkovitz United States 46032 Indiana Kingsmill Drive, 10737, Carmel, U.S.A. (72) Inventor Kenneth Jeff Slasher, USA 46217 Count Turf Coat, 8660, Indianapolis, Indiana

Claims (4)

[Claims] 1. Formula I: ## STR1 ## Wherein R ¹ is —H, —OH, —O (C ₁ -C ₄ alkyl), —OC
OAr, -O (CO) OAr ( Ar is phenyl or substituted _{phenyl), - OCO (C 1 -C} 6 alkyl), - O
(CO) O (C ₁ -C ₆ alkyl) or —OSO ₂ (C ₂ −
Be a C ₆ alkyl); R ² is -H, -Cl, -F, -O
H, -O (C ₁ -C ₄ alkyl), - OCOAr, -O (C
O) OAr (Ar is phenyl or substituted _{phenyl), - OCO (C 1 -C} 6 alkyl), - O (CO) O (C 1
-C ₆ alkyl), or -OSO ₂ (C ₂ -C ₆ alkyl)
R ³ is 1-piperidinyl, 1-pyrrolidinyl,
Methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino; R ⁴ is —H, C ₁ -C ₅ alkyl, —CO 2
Ar, - (CO) H, -CO (C 1 -C 6 alkyl), - SO ₂
(C ₂ -C ₆ alkyl), or —SO ₂ Ar, where Ar is phenyl or substituted phenyl; and n is 2
Or 3] or a pharmaceutically acceptable salt or solvate thereof. 2. A compound of formula II: Wherein R ^1a is —H or —OR ⁷ (R ⁷ is a hydroxy protecting group); R ^2a is —H, —Cl, —F, or —OR ⁷
(R ⁷ is a hydroxy protecting group); R ^4a is —C
O (C ₁ -C ₄ alkyl) or — (CO) H; and R ⁶ is a hydroxy protected which can be selectively removed in the presence of —H or R ^{8, where} R ⁸ is —OR ⁷ Is the base)
Is a compound of the formula: 3. A compound of formula VII: Wherein R ^1a is —H or —OR ⁷ (R ⁷ is a hydroxy protecting group); R ^2a is —H, —Cl, —F, or —OR ⁷
(R ⁷ is a hydroxy protecting group); R ^4a is —C
O (C ₁ -C ₄ alkyl) or — (CO) H; n is 2
Or 3; and Q is a leaving group]. 4. A pharmaceutical preparation for anti-menopausal syndrome, comprising:
A pharmaceutical formulation comprising a compound of formula I according to claim 1 as an active ingredient, together with one or more pharmaceutically acceptable excipients, carriers or diluents.